Advancing Tourette Syndrome genetics using bioinformatics and genome biology Tourette Syndrome (TS) is a childhood-onset, neuropsychiatric disorder that is highly heritable, though discovery of definitive TS susceptibility genes has been challenging. This Independent Scientist Award (K02) will provide the candidate with additional training in bioinformatics and analysis of genome biology data to provide him with the remaining experience, knowledge and skills needed to direct a comprehensive human genetics research program aimed at discovery and functional analysis of disease variants for TS and related neurodevelopmental disorders. The research plan consists of: 1) a genome-wide association study of 3021 new TS cases and 3536 ancestry-matched controls to examine the role of common gene variants in TS susceptibility; 2) an analysis of next-generation sequencing data containing >90% of all protein-coding regions of the genome (whole exome sequencing) in TS parent-proband trios to explore the contribution of rare, damaging loss-of-function mutations in the disorder; 3) an integrative analysis of genes implicated by the studies in Aims 1 and 2 combined with biological data of gene expression in various brain tissues across different developmental time points to identify the specific biological pathways that may underlie the TS disease process. The proposed study will be conducted at Massachusetts General Hospital in collaboration with consultants at MGH, the Broad Institute of Harvard and MIT as well as the University of Chicago, each who have complementary expertise in computational biology, analysis of next-generation sequencing data, and integration of disease-associated DNA variation with epigenomic and gene expression data. The career development plan includes a didactic component combining targeted coursework and computational biology workshops with longitudinal supervision of data analysis. This proposal provides a unique and exciting opportunity to rapidly advance the goal of identifying the biological basis of this complex and important model neuropsychiatric disorder which in the future could lead to new avenues for disease treatment and/or prevention.